Effect of alpha1-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro.

AIMS: Since alpha1-acid glycoprotein (AGP) levels may be raised during HIV infection, we have examined in vitro the effect of increasing the concentration of AGP on the intracellular accumulation of the HIV protease inhibitors saquinavir (SQV), ritonavir (RTV) and indinavir (IDV).
METHODS: U937 cells (5 x 10(6) cells in 5 ml RPMI growth medium) were incubated at 37 degrees C for 18 h with [14C]-SQV (0.1 microCi), [3H]-RTV and [3H]-IDV (0.135 microCi) to a final concentration of 1 microM in the presence of 0, 0.5 and 2.0 mg x ml(-1) AGP. Following extraction in 60% methanol the intracellular drug concentration was determined by liquid scintillation counting.
RESULTS: Binding to AGP (2.0 mg x ml(-1)) reduced the mean intracellular concentration of SQV from 31.5 microM to 7.4 microM (P < 0.0001; 95% CI 19.4-28.8). RTV concentration was also reduced (8.8 microM to 1.6 microM; P < 0.0001; 95% CI 5.4-9.0) as was the concentration of IDV (3.0 microM to 1.5 microM; P < 0.0001; 95% CI 1.1-1.9).
CONCLUSIONS: Reduced intracellular protease inhibitor concentrations in the presence of increasing concentrations of AGP will certainly impact on the antiviral activity in vitro. However, since protease inhibitors are high clearance drugs, free drug concentration will likely remain unaffected in the presence of elevated AGP during chronic oral dosing although there will be an increase in total plasma drug concentration.